1. Field of the Invention
The present invention relates to a fluid management apparatus which provides format conversion between a plurality of fluid inlets and a plurality of fluid outlets and is suitable, for example, for use in a dispensing head.
The fluid management apparatus in accordance with the invention can be advantageously used, for example, in the dispensing head of an apparatus for applying at least one microdroplet to a substrate, with which a plurality of microdroplets can be applied to a substrate. In particular, the fluid management apparatus in accordance with the invention is suitable for being used in the production of so-called biochips, in which a plurality of different analytes are applied to a substrate in order to detect a different substances in an unknown sample. In addition, the present invention is suitable for implementing a format conversion between microtiter plates having different raster dimensions.
The increasing decryption of genomes of humans, animals and plants provides for a multitude of new possibilities, ranging from diagnosis of genetic diseases to a substantially accelerated search for active substances which are interesting from a pharmaceutical point of view. The above-mentioned biochips will in the future be used, for example, to examine food stuffs with regard to a multitude of possible, genetically manipulated components. In a further field of application, such biochips may be used to determine the exact genetic defect in genetic diseases so as to derive therefrom the ideal strategy for treating the disease.
The biochips which may be used for such applications typically consists of a carrier material, i.e. a substrate, onto which a multitude of different substances are applied in the form of a raster. Typical raster spacings in the array range from 100 μm to 1,000 μm. The diversity of the different substances, which are referred to as so-called analytes, on one biochip ranges from only a few different substances to several 100,000 different substances per substrate, depending on the application. With each of these different analytes, a specific substance can be detected in an unknown sample.
If an unknown sample liquid is applied to a biochip, certain analytes show reactions which can be detected by means of suitable methods, i.e. by fluorescence detection. Here, the number of the different analytes on the biochip corresponds to the number of the different components in the unknown sample liquid, which can be analyzed simultaneously using the respective biochip. Such a biochip is a diagnose tool with which an unknown sample can be examined simultaneously and specifically with regard to a multitude of constituents.
2. Description of Prior Art
Currently, three principally different methods are known for applying the analytes onto a substrate so as to produce such a biochip. These methods are employed alternatively, depending on the number of biochips required or on the number of analytes required per chip.
The first method is referred to as “contact printing” wherein a bundle of steel capillaries is used, the interior of which is filled with different analytes. This bundle of steel capillaries is stamped onto the substrate. When the bundle is lifted off, the analytes will remain attached to the substrate in the form of microdroplets. In this method, however, the quality of the printing pattern is very strongly determined by the action of capillary forces and therefore depends on a multitude of critical parameters, for example on the quality and the coating of the surface of the substrate, on the exact geometry of the nozzle and, above all, on the media used. In addition, the method is highly susceptible to contamination of the substrate and of the nozzles. This above-described method is suited for a variety of analytes of up to several 100 per substrate.
In a second method for producing biochips, the so-called “spotting”, mostly so-called microdispensers are employed which are capable, similarly to ink printers, of firing individual microdroplets of a liquid onto a substrate upon a corresponding control command. Such a method is referred to as “drop-on-demand”. Such microdispensers are commercially available from several companies. The advantage of this method is that the analytes may be applied onto a substrate without direct contact, the influence of capillary forces having no significance. However, a major problem is that it is very expensive and rather difficult to arrange a multitude of nozzles, which are all supplied with different media, in parallel or in an array. The limiting element here is actuating means as well as media logistics, which are not miniaturizable to the desired extent.
As a third method for manufacturing biochips the so-called “synthesis method” is currently used, wherein the analytes, which typically consist of a chain of nucleic acids which are attached to one another, are chemically produced on the substrate, i.e. synthesized. For demarcating the spatial position of the various analytes, methods are used such as are known from microelectronics, for example lithography methods using mask techniques. This synthesis method is by far the most expensive one among the methods mentioned, which allows, however, to produce the largest variety of analytes on a chip, in the order of magnitude of 100,000 different analytes per substrate.
From WO-A-93/09668, methods are known of forming polymers having different monomer sequences on a single substrate, wherein, via a plurality of channels formed in a channel block, monomers are brought to selected regions for synthesizing polymers at these regions. For this purpose, the channel blocks comprise channels which are opened toward the outside in a surface and which comprise an inlet and an outlet formed in the opposite surface of the channel block. A desired reagent is supplied to the channel via the inlet opening, whereas a vacuum pump is connected to the outlet opening.
WO-A-97/45730 relates to a method and apparatus for supplying solutions to an array of cells. To this end, an array of cells is formed on a substrate. A further substrate has recesses and microchannels connected to the recesses, which channels enable supplying a fluid to the recesses. The cells are introduced into the recesses whereupon solutions are brought into the recesses through the channels for treating the cells. The microchannels are connected with microcapillary tubes via which solutions can be supplied, for example using a microtiter plate.